Multi-Metallic Nanosheets Reshaping Immunosuppressive Tumor Microenvironment through Augmenting cGAS-STING Innate Activation and Adaptive Immune Responses for Cancer Immunotherapy.

The highly immunosuppressive tumor microenvironment (TME) restricts the efficient activation of immune responses. To restore the surveillance of the immune system for robust activation, vast efforts are devoted to normalizing the TME. Here, a manganese-doped layered double hydroxide (Mn-LDH) is developed for potent anti-tumor immunity by reversing TME. Mn-LDH is synthesized via a one-step hydrothermal method. In addition to the inherent proton neutralization capacity of LDH, the introduction of manganese oxide endows LDH with an additional ability to produce oxygen. Mn-LDH effectively releases Mn2+ and Mg2+ upon exposure to TME with high levels of H+ and H2O2, which activates synthase-stimulator of interferon genes pathway and maintains the cytotoxicity of CD8+ T cells respectively, achieving a cascade-like role in innate and adaptive immunity. The locally administered Mn-LDH facilitated a "hot" network consisting of mature dendritic cells, M1-phenotype macrophages, as well as cytotoxic and helper T cells, significantly inhibiting the growth of primary and distal tumors. Moreover, the photothermal conversion capacity of Mn-LDH sparks more robust therapeutic effects in large established tumor models with a single administration and irradiation. Overall, this study guides the rational design of TME-modulating immunotherapeutics for robust immune activation, providing a clinical candidate for next-generation cancer immunotherapy.

Long-life triclosan exposure induces ADHD-like behavior in rats via prefrontal cortex dopaminergic deficiency.

In recent years, exposure to triclosan (TCS) has been linked to an increase in psychiatric disorders. Nonetheless, the precise mechanisms of this occurrence remain elusive. Therefore, this study developed a long-life TCS-exposed rat model, an SH-SY5Y cell model, and an atomoxetine hydrochloride (ATX) treatment model to explore and validate the neurobehavioral mechanisms of TCS from multiple perspectives. In the long-life TCS-exposed model, pregnant rats received either 0 mg/kg (control) or 50 mg/kg TCS by oral gavage throughout pregnancy, lactation, and weaning of their offspring (up to 8 weeks old). In the ATX treatment model, weanling rats received daily injections of either 0 mg/kg (control) or 3 mg/kg ATX via intraperitoneal injection until they reached 8 weeks old. Unlike the TCS model, ATX exposure only occurred after the pups were weaned. The results indicated that long-life TCS exposure led to attention-deficit hyperactivity disorder (ADHD)-like behaviors in male offspring rats accompanied by dopamine-related mRNA and protein expression imbalances in the prefrontal cortex (PFC). Moreover, in vitro experiments also confirmed these findings. Mechanistically, TCS reduced dopamine (DA) synthesis, release, and transmission, and increased reuptake in PFC, thereby reducing synaptic gap DA levels and causing dopaminergic deficits. Additional experiments revealed that increased DA concentration in PFC by ATX effectively alleviated TCS-induced ADHD-like behavior in male offspring rats. These findings suggest that long-life TCS exposure causes ADHD-like behavior in male offspring rats through dopaminergic deficits. Furthermore, ATX treatment not only reduce symptoms in the rats, but also reveals valuable insights into the neurotoxic mechanisms induced by TCS.

Cardiac Arrhythmia Risk after Anti-Cancer Drug Exposure and Related Disease Molecular Imaging Outlook: A Systematic Review, Meta-Analysis, and Network Meta-Analysis.

BACKGROUND: Chemotherapy is the main first-line treatment, but there is a problem of adverse reactions to systemic drugs. Chemotherapeutic agents may cause adverse effects on the body, influencing the prognosis. Whether the clinical application of anthracyclines is associated with an increased arrhythmic risk remains controversial. To evaluate the arrhythmic risk of anthracyclines as a class, and the comparative risk for each drug, we conducted a systematic review, meta-analysis, and network meta-analysis. METHODS: PubMed, Web of Science, EMBASE, and the Cochrane Library were searched, up to March 2022, for randomized controlled trials, cohort studies, and case-control studies that investigated the association between anthracyclines treatment and the risk of arrhythmia. We followed the PRISMA 2020 guidelines for data selection and extraction. Outcomes were pooled using fixed effects models in cohort studies and randomized controlled studies, and random models in single-arm studies. Direct and indirect comparisons in network meta-analysis were performed using frequentist methods. RESULTS: In total, 4 cohort studies, 8 RCTs, and 18 single-arm studies were included in our analysis. Anthracyclines' use was associated with a statistically significant 90% increase in the risk of arrhythmia (odds ratio [OR] 1.90; 95% confidence interval [CI] 1.62-2.24) and a 114% increase in the risk of supraventricular arrhythmia (OR 2.14; 95% CI 1.18-3.89). And the single-arm studies also indicated that the incidence of arrhythmia rate is 20% and the 95% CI is 15/100-25/100. Epirubicin ranked most likely to have the highest risk of arrhythmia compared with non-anthracycline antineoplastic drugs in the analysis (OR 43.07 [95% CI 2.80-2105.83]) by network meta-analysis. CONCLUSIONS: Our findings show a significant association between anthracyclines' use and an increased risk of arrhythmia, especially supraventricular arrhythmia. Epirubicin ranked with the highest probability of arrhythmia. These results indicated that cardiac rhythm should be strictly monitored during the application of anthracyclines in clinical practice, and a possible therapy for anthracycline-associated arrhythmia should be explored. Molecular imaging technology is an important means to study the mechanism of drug action on cardiac electrophysiology in the future. By imaging molecular targets in cardiac cells, the effects of drugs on the electrophysiological properties of cardiac cells can be understood, which provides information for the development of safer and more effective drugs.

Neurotoxic effects of triclosan in adolescent mice: Pyruvate kinase M2 dimer regulated Signal transducer and activator of transcription 3 phosphorylation mediated microglia activation and neuroinflammation.

Triclosan (TCS), a commonly used antibacterial agent, is associated with various harmful effects on mammalian neurodevelopment, particularly when exposed prenatally. This study investigated the impact of long-term exposure to TCS on the prefrontal cortex development in adolescent mice. We evaluated the motor ability, motor coordination, and anxiety behavior of mice using open field tests (OFT) and elevated cross maze tests (EPM). An increase in movement distance, number of passes through the central area, and open arm retention time was observed in mice treated with TCS. Hematoxylin eosin staining and Nissl staining also showed significant adverse reactions in the brain tissue of TCS-exposed group. TCS induced microglia activation and increased inflammatory factors expression in the prefrontal cortex. TCS also increased the expression of pyruvate kinase M2 (PKM2), thereby elevating the levels of PKM2 dimer, which entered the nucleus. Treatment with TEPP46 (PKM2 dimer nuclear translocation inhibitor) blocked the expression of inflammatory factors induced by TCS. TCS induced the phosphorylation of nuclear signal transducer and activator of transcription 3 (STAT3) in vivo and in vitro, upregulating the levels of inflammatory cytokines. The results also demonstrated the binding of PKM2 to STAT3, which promoted STAT3 phosphorylation at the Tyr705 site, thereby regulating the expression of inflammatory factors. These findings highlight the role of PKM2-regulated STAT3 phosphorylation in TCS-induced behavioral disorders in adolescents and propose a reliable treatment target for TCS.

Study on Static Mechanical Properties and Numerical Simulation of Coral Aggregate Seawater Shotcrete with Reasonable Mix Proportion.

This study aims to explore the static mechanical characteristics of coral aggregate seawater shotcrete (CASS) using an appropriate mix proportion. The orthogonal experiments consisting of four-factor and three-level were conducted to explore an optimal mix proportion of CASS. On a macro-scale, quasi-static compression and splitting tests of CASS with optimal mix proportion at various curing ages employed a combination of acoustic emission (AE) and digital image correlation (DIC) techniques were carried out using an electro-hydraulic servo-controlled test machine. A comparative analysis of static mechanical properties at different curing ages was conducted between the CASS and ordinary aggregate seawater shotcrete (OASS). On a micro-scale, the numerical specimens based on particle flow code (PFC) were subjected to multi-level microcracks division for quantitive analysis of the failure mechanism of specimens. The results show that the optimal mix proportion of CASS consists of 700 kg/m3 of cementitious materials content, a water-binder ratio of 0.45, a sand ratio of 60%, and a dosage of 8% for the accelerator amount. The tensile failure is the primary failure mechanism under uniaxial compression and Brazilian splitting, and the specimens will be closer to the brittle material with increased curing age. The Brazilian splitting failure caused by the arc-shaped main crack initiates from the loading points and propagates along the loading line to the center. Compared with OASS, the CASS has an approximately equal early and low later strength mainly because of the minerals' filling or unfilling effect on coral pores. The rate of increase in CASS is swifter during the initial strength phase and decelerates during the subsequent stages of strength development. The failure in CASS is experienced primarily within the cement mortar and bonding surface between the cement mortar and aggregate.

Enhanced TfR1 Recognition of Myocardial Injury after Acute Myocardial Infarction with Cardiac Fibrosis via Pre-Degrading Excess Fibrotic Collagen.

The fibrosis process after myocardial infarction (MI) results in a decline in cardiac function due to fibrotic collagen deposition and contrast agents' metabolic disorders, posing a significant challenge to conventional imaging strategies in making heart damage clear in the fibrosis microenvironment. To address this issue, we developed an imaging strategy. Specifically, we pretreated myocardial fibrotic collagen with collagenase I combined with human serum albumin (HSA-C) and subsequently visualized the site of cardiac injury by near-infrared (NIR) fluorescence imaging using an optical contrast agent (CI, CRT-indocyanine green) targeting transferrin receptor 1 peptides (CRT). The key point of this strategy is that pretreatment with HSA-C can reduce background signal interference in the fibrotic tissue while enhancing CI uptake at the heart lesion site, making the boundary between the injured heart tissue and the normal myocardium clearer. Our results showed that compared to that in the untargeted group, the normalized fluorescence intensity of cardiac damage detected by NIR in the targeted group increased 1.28-fold. The normalized fluorescence intensity increased 1.21-fold in the pretreatment group of the targeted groups. These data demonstrate the feasibility of applying pretreated fibrotic collagen and NIR contrast agents targeting TfR1 to identify ferroptosis at sites of cardiac injury, and its clinical value in the management of patients with MI needs further study.

Elucidating Iron Metabolism through Molecular Imaging.

Iron is essential for many physiological processes, and the dysregulation of its metabolism is implicated in the pathogenesis of various diseases. Recent advances in iron metabolism research have revealed multiple complex pathways critical for maintaining iron homeostasis. Molecular imaging, an interdisciplinary imaging technique, has shown considerable promise in advancing research on iron metabolism. Here, we comprehensively review the multifaceted roles of iron at the cellular and systemic levels (along with the complex regulatory mechanisms of iron metabolism), elucidate appropriate imaging methods, and summarize their utility and fundamental principles in diagnosing and treating diseases related to iron metabolism. Utilizing molecular imaging technology to deeply understand the complexities of iron metabolism and its critical role in physiological and pathological processes offers new possibilities for early disease diagnosis, treatment monitoring, and the development of novel therapies. Despite technological limitations and the need to ensure the biological relevance and clinical applicability of imaging results, molecular imaging technology's potential to reveal the iron metabolic process is unparalleled, providing new insights into the link between iron metabolism abnormalities and various diseases.

Effects of warming on rice production and metabolism process associated with greenhouse gas emissions.

Evaluating the impact of global warming on rice production and greenhouse gas (GHG) emissions is critical for ensuring food security and mitigating the consequences of climate change. Nonetheless, the impacts of warming on crop production, GHG emissions, and microbial mechanisms in the single-cropping rice systems remain unclear. Here, a two-year field experiment was conducted to explore the effects of warming (increased by 2.7-3.0 °C on average) in the rice growing season on crop production and functional microorganisms associated with GHG emissions. Results showed that warming resulted in significant reduction (p < 0.01) in the aboveground biomass and grain yield as well as in grain weight, the number of spikelets per panicle, and the seed-setting rate. However, it caused a significant increase (p < 0.01) in the number of panicles by 15.6 % and 34.9 %, respectively. Furthermore, warming significantly increased (p < 0.01) seasonal methane (CH4) emissions but reduced nitrous oxide (N2O) emissions, particularly in 2022.The relative abundance of genes associated with CH4 metabolism and nitrogen metabolism was increased by 40.7 % and 32.7 %, respectively, in response to warming. Moreover, warming had a positive impact on the abundance of genes related to CH4 production and oxidation processes but did not affect the denitrification processes associated with N2O production. These results showed that warming decreased rice yield and biomass in the single cropping rice system but increased CH4 emissions and global warming potential. Taken together, to address the increasing food demand of a growing population and mitigate the impacts of global warming, it is imperative to duce GHG emissions and enhance crop yields.

Preparation of landscape gardening soil using undersized fraction from aged MSW by EDTA or citric acid coupled with humic acid: Effect assessment, properties, and optimization.

Undersized fraction from aged municipal solid waste (UFAMSW), as a kind of soil-like material, has been proved effective in providing a large amount of organic matter and nutrients for soil and plants. The characteristics and effectiveness of heavy metal pollution removal in UFAMSW attracted tremendous research interest from scientists recently. In this study, the heavy metal removal efficiencies and bioavailability of washing on contaminated UFAMSW were evaluated with three washing reagents including ethylene diamine tetra acetic acid (EDTA), citric acid (CA), and humic acid (HA). The effects of chelating agent concentration, pH, and washing time on metal removal were investigated and response surface methodology (RSM) was employed to optimize the washing conditions. The results indicated that the removal efficiencies of Cu, Zn, and Mn could be 53.68%, 52.12%, and 30.63% by EDTA/HA washing and 42.36%, 39.67% and 28.49% by CA/HA washing, respectively. The European Community Bureau of Reference (BCR) sequential extraction was applied to analyze the fraction change of heavy metals in UFAMSW before and after washing, and it was found that chelating agent combined with HA could contribute to the removal of the exchangeable fraction. Physical and chemical properties of UFAMSW were improved to some extent after washing with mixed HA and chelating agent and could achieve the quality standard of landscape gardening soil. Accordingly, the mixture of HA and other chelating agents could be a promising washing process for preparation of landscape gardening soil using UFAMSW.Implications: Our manuscript studies the removal of heavy metals from the contaminated undersized fraction from aged municipal solid waste (UFAMSW). UFAMSW, as a kind of soil-like material, has been proved effective in providing a large amount of organic matter and nutrients for soil and plants however often limited by heavy metal pollution. The UFAMSW used in this experiment was collected after the excavation and screening-sorting of aged refuse from Changshankou Domestic Waste Sanitary Landfill in Wuhan City, Hubei Province, Southern China. This study investigated the effects of EDTA, CA, HA, mixed EDTA/HA, and mixed CA/HA washing on heavy metal removal (Cu, Zn, and Mn), bioavailability of residual heavy metal and properties. The effects of chelating agent concentration, pH, and washing time on metal removal were investigated and then response surface methodology was employed to optimize the washing conditions. The results showed that washing by CA/HA and EDTA/HA, had a higher removal efficiency of heavy metals (Cu, Zn, and Mn) in UFAMSW compared to single HA. Meanwhile, HA has a higher removal for exchangeable fraction of heavy metals, the exchangeable concentration of Cu, Zn, and Mn in CA/HA and EDTA/HA washed UFAMSW were lower compared with UFAMSW washed by single CA and EDTA. Thus, mixing HA with EDTA or CA makes a less risk to environmental and the removal efficiency is acceptable. Additionally, CA/HA and EDTA/HA washing tend to improve soil physicochemical properties and soil fertility. Thus, mixing HA with different washing agent are potential methods for preparation of landscape gardening soil using UFAMSW.

Effects of selenium nanoparticles produced by Lactobacillus acidophilus HN23 on lipid deposition in WRL68 cells.

Selenium is an essential trace element for most organisms, protecting cells from oxidative damage caused by free radicals and serving as an adjunctive treatment for non-alcoholic fatty liver disease (NAFLD). In this study, We used the lactic acid bacterium Lactobacillus acidophilus HN23 to reduce tetra-valent sodium selenite into particulate matter, and analyzed it through inductively coupled plasma mass spectrometry (ICP-MS), scanning electron microscopy (SEM), X-ray diffraction energy dispersive spectrometry (EDS), and Fourier transform infrared spectroscopy (FTIR). We found that it consisted of selenium nanoparticles (SeNPs) with a mass composition of 65.8 % zero-valent selenium and some polysaccharide and polypeptide compounds, with particle sizes ranging from 60 to 300 nm. We also detected that SeNPs were much less toxic to cells than selenite. We further used free fatty acids (FFA)-induced WRL68 fatty liver cell model to study the therapeutic effect of SeNPs on NAFLD. The results show that SeNPs are more effective than selenite in reducing lipid deposition, increasing mitochondrial membrane potential (MMP) and antioxidant capacity of WRL68 cells, which is attributed to the chemical valence state of selenium and organic composition in SeNPs. In conclusion, SeNPs produced by probiotics L. acidophilus had the potential to alleviate NAFLD by reducing hepatocyte lipid deposition and oxidative damage. This study may open a new avenue for SeNPs drug development to treat NAFLD.

Triclosan induces liver injury in long-life exposed mice via activation of TLR4/NF-κB/NLRP3 pathway.

Triclosan (TCS) is a widely used synthetic, with broad-spectrum antibacterial properties found in both pharmaceuticals and personal care products. More specifically, it is hepatotoxic in rodents and exhibits differential effects in mice and humans. However, the mechanisms underlying TCS-induced liver toxicity have not been elucidated. This study examined the role of the toll-like receptor 4 (TLR4)/ nuclear factor kappa B (NF-κB)/ nod-like receptor protein 3 (NLRP3) pathway in TCS-exposed liver toxicity by established a long-life TCS-exposed mice liver injury model. The 24 C57BL/6 pregnant mice exposed to TCS (0, 50 and 100 mg/kg) every day during the gestation and nursing period. After weaning, the male mice were left to continue administrate with TCS until 8 weeks of age. Then, mice in each group were sacrificed for investigation. Long-life exposure to TCS resulted in a reduction of body weight in growth mice. TCS exposure caused the increase of serum ALT, AST and ALP. The situation of inflammatory cell infiltration, macrophage recruitment and collagen fiber deposition in TCS-exposed mice liver tissues were performed by histological analysis including hematoxylin-eosin, Masson, Sirius red, and immunohistochemistry staining. Protein expression levels in TLR4/NF-κB/NLRP3 pathway was measured through Western blot, and the NLRP3 inflammasome activation was measured using real-time quantitative PCR (RT-qPCR). The results showed that exposure to TCS elevated TLR4, myeloid differentiation factor 88 (Myd88), TNF receptor associated factor 6 (TRAF6), enhanced NF-κB activation, and affected NLRP3 inflammasome activation in mice liver. Collectively, these findings indicate that long-life exposure to TCS-induced mice by upregulating the TLR4-Myd88-TRAF6 pathway, activating the NF-κB signaling cascade, initiating the NLRP3 inflammasome pathway, and ultimately leading to liver injury, including inflammation, hepatocyte pyroptosis and hepatofibrosis. Henceforth, the TLR4/NF-κB/NLRP3 pathway may now provide a theoretical basis and valuable therapeutic targets for overcoming TCS-induced liver toxicity.

Engineered Bio-Based Hydrogels for Cancer Immunotherapy.

Immunotherapy represents a revolutionary paradigm in cancer management, showcasing its potential to impede tumor metastasis and recurrence. Nonetheless, challenges including limited therapeutic efficacy and severe immune-related side effects are frequently encountered, especially in solid tumors. Hydrogels, a class of versatile materials featuring well-hydrated structures widely used in biomedicine, offer a promising platform for encapsulating and releasing small molecule drugs, biomacromolecules, and cells in a controlled manner. Immunomodulatory hydrogels present a unique capability for augmenting immune activation and mitigating systemic toxicity through encapsulation of multiple components and localized administration. Notably, hydrogels based on biopolymers have gained significant interest owing to their biocompatibility, environmental friendliness, and ease of production. This review delves into the recent advances in bio-based hydrogels in cancer immunotherapy and synergistic combinatorial approaches, highlighting their diverse applications. It is anticipated that this review will guide the rational design of hydrogels in the field of cancer immunotherapy, fostering clinical translation and ultimately benefiting patients.

Efficacy and safety of Qingda granule versus valsartan capsule in Chinese grade 1 hypertensive patients with low-moderate risk: A randomized, double-blind, double dummy, non-inferiority, multi-center trial.

BACKGROUND: The efficacy and safety of Qingda granule (QDG) in managing blood pressure (BP) among grade 1 hypertensive patients with low-moderate risk remain uncertain. METHODS: In the randomized, double-blind, double dummy, non-inferiority and multicenter trial, 552 patients with grade 1 hypertension at low-moderate risk were assigned at a ratio of 1:1 to receive either QDG or valsartan for 4 weeks, followed up by a subsequent 4 weeks. RESULTS: Post-treatment, clinic systolic/diastolic BPs (SBP/DBP) were reduced by a mean change of 9.18/4.04 mm Hg in the QDG group and 9.85/5.05 mm Hg in the valsartan group (SBP P = 0.47, DBP P = 0.16). Similarly, 24-hour, daytime and nighttime BPs were proportional in both groups (P > 0.05) after 4 weeks treatment. After discontinuing medications for 4 weeks, the mean reduction of clinic SBP/DBP were 0.29/0.57 mm Hg in the QDG group compared to -1.59/-0.48 mm Hg in the valsartan group (SBP P = 0.04, DBP P = 0.04). Simultaneously, the 24-hour SBP/DBP were reduced by 0.9/0.31 mm Hg in the QDG group and -1.66/-1.08 mm Hg in the valsartan group (SBP P = 0.006, DBP P = 0.02). And similar results were observed regarding the outcomes of daytime and nighttime BPs. There was no difference in occurrence of adverse events between two groups (P > 0.05). CONCLUSION: QDG proves to be efficacious for grade 1 hypertension at a low-to-medium risk, even after discontinuation of the medication for 4 weeks. These findings provide a promising option for managing grade 1 hypertension and suggest the potential for maintaining stable BP through intermittent administration of QDG. TRIAL REGISTRATION: ChiCTR2000033890.